What is psychedelic-assisted therapy?

Psychedelic-assisted therapy is a form of psychiatric treatment that combines a pharmacological agent (a psychedelic or dissociative drug) with intensive psychotherapy — in a carefully controlled therapeutic setting, with trained therapists present throughout the drug session. The model: the drug creates a temporary window of increased neuroplasticity and psychological openness; the therapy provides the structure to use that window for meaningful psychological change. It is radically different from recreational drug use: it involves multiple preparatory therapy sessions; a professionally monitored 4-8 hour drug session; and multiple integration therapy sessions after. Currently available or in late-stage trials: esketamine (FDA-approved for TRD); psilocybin (Australia-approved for TRD; FDA Breakthrough designation); MDMA (Australia-approved for PTSD; FDA decision pending).

How does esketamine work and why is it important?

Esketamine (Spravato) works through a completely different mechanism from SSRIs, SNRIs and tricyclic antidepressants — all of which work on the monoamine system (serotonin, noradrenaline, dopamine). Esketamine is an NMDA receptor antagonist — it blocks glutamate receptors, triggering a cascade: glutamate surge → AMPA receptor activation → BDNF (brain-derived neurotrophic factor) release → synaptogenesis (formation of new synaptic connections in the prefrontal cortex, which are reduced in depression). This produces antidepressant effects within 2-4 hours — dramatically faster than the 4-6 weeks required for SSRIs. It is approved specifically for treatment-resistant depression (failed 2+ antidepressants) and, in the USA, for depressive symptoms in adults with major depressive disorder with acute suicidal ideation. It must be administered in a certified healthcare setting with 2-hour monitoring (due to dissociative effects, blood pressure changes and potential for misuse).

Is psilocybin medicine now?

Not yet in most countries — but it is in some: Australia's Therapeutic Goods Administration (TGA) approved psilocybin for treatment-resistant depression in July 2023, making Australia the first country to formally recognise it as medicine. Oregon (USA) established licensed therapeutic psilocybin service centres in 2023. In most countries, psilocybin remains a Schedule I controlled substance, meaning it can only be used in approved clinical trials. The FDA awarded two Breakthrough Therapy Designations but the advisory committee voted against approval in June 2024, citing the need for larger Phase 3 trials. Approval could follow in 2025-2028 if Phase 3 data are compelling. The current status: genuinely promising Phase 2 evidence; not yet FDA/EMA-approved; legal clinical access growing in Australia and some US states.

Who is a candidate for psychedelic therapy?

Current approved indications: treatment-resistant depression (esketamine; psilocybin in Australia) — people who have failed at least two adequate antidepressant trials. PTSD (MDMA in Australia). Future potential (based on clinical trial data): major depressive disorder (psilocybin Phase 3 trials ongoing); end-of-life anxiety (psilocybin has the strongest evidence here — multiple high-quality trials showing dramatic reductions in existential anxiety and "death distress" in cancer patients); addiction (psilocybin for tobacco addiction — Johns Hopkins pilot showing 80% abstinence at 6 months, extraordinary vs standard treatments). Contraindicated: personal or family history of psychosis or bipolar I; active suicidality with plan; cardiovascular disease (ketamine/MDMA); pregnancy.

What are the risks of psychedelic therapy?

Esketamine: common — dissociative effects, nausea, dizziness (during the 2-hour monitoring period); blood pressure increase; risk of sedation. Uncommon — potential for misuse (administered in clinic, not take-home). Psilocybin: common — "challenging experiences" (fear, anxiety, confusion during the session, in 40-60% of subjects — manageable with therapist support); emotional processing during integration. Rare — HPPD (hallucinogen persisting perception disorder: visual phenomena persisting after the experience, in approximately 1-4%); psychological decompensation in people with unrecognised vulnerability. Contraindication: psychosis risk in susceptible individuals (history of personal/family psychosis). MDMA: increased heart rate and blood pressure (requires cardiovascular screening); hyperthermia risk; serotonin syndrome if combined with SSRIs (sessions require SSRIs to be tapered before treatment).

How does GMJ News cover psychedelic therapy?

GMJ News covers esketamine FDA approval and NMDA mechanism; psilocybin FDA Breakthrough status and Australia approval; COMPASS Phase 2b trial results; MAPS MDMA/PTSD Phase 3 and Australia approval; the therapeutic model (not recreational use); DMN and neuroplasticity mechanism; contraindications; the 25-year research blackout and renaissance; HPPD risk; and Georgia/PHIG implications for psychiatry practice. GMJ position: psychedelic therapy represents a genuine paradigm shift in psychiatry for treatment-resistant conditions — esketamine is established medicine; psilocybin and MDMA are evidence-based emerging treatments approaching regulatory approval in multiple jurisdictions.

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Psychedelic Therapy

GMJ News knowledge hub · last reviewed September 2026 · Georgian Medical Journal

Summary Statistics Glossary GMJ news FAQ Documents Organizations Research

Psychedelic-assisted therapy — combining pharmacological agents that produce profound alterations in consciousness with structured psychotherapeutic support — has undergone a scientific renaissance after 25 years of prohibition-enforced research blackout, with esketamine (Spravato) receiving FDA approval in 2019 as the first truly novel antidepressant mechanism in decades for treatment-resistant depression, psilocybin awarded two FDA Breakthrough Therapy designations (for treatment-resistant depression 2018 and major depressive disorder 2019), and Australia becoming the first country to approve MDMA for PTSD and psilocybin for TRD in 2023 — the most significant paradigm shift in psychiatry since the introduction of SSRIs in the 1980s (WHO). The therapeutic model is radically different from standard pharmacotherapy: psychedelic therapy is not a drug you take — it is a drug-assisted therapeutic process, requiring preparation sessions, a guided dosing session with trained therapists present throughout, and integration therapy afterward, targeting the window of neuroplasticity that these agents create.

Key messages

Esketamine (Spravato) — FDA approved 2019 — first new antidepressant mechanism in 30 years

Esketamine (Spravato, Janssen) nasal spray — the S-enantiomer of ketamine, an NMDA receptor antagonist — received FDA approval in March 2019 for treatment-resistant depression (TRD). It produces rapid antidepressant effects within 2-4 hours — in contrast to SSRIs/SNRIs which require 4-6 weeks. This was the first truly novel antidepressant mechanism approved in approximately 30 years, and a paradigm shift in psychiatry.

Psilocybin — two FDA Breakthrough Therapy designations

Psilocybin received FDA Breakthrough Therapy Designation for treatment-resistant depression (2018, COMPASS Pathways) and major depressive disorder (2019, Johns Hopkins). COMPASS Phase 2b trial: 25mg psilocybin produced 29% remission at 3 weeks vs 8% placebo (NEJM Evidence, 2022). The FDA advisory committee voted against full approval in June 2024 — requiring larger Phase 3 trials before approval. Australia approved psilocybin for TRD in July 2023 — the first country globally.

MDMA for PTSD — Australia approved 2023; FDA advisory voted against in 2024

MAPS (Multidisciplinary Association for Psychedelic Studies) conducted Phase 3 trials of MDMA-assisted therapy for PTSD — showing approximately 67% PTSD symptom improvement vs 32% placebo (NEJM Evidence, 2023). Australia's TGA approved MDMA for PTSD in July 2023. The US FDA advisory committee voted against approval in June 2024, citing concerns about trial methodology (functional unblinding) and small Phase 3 dataset — requiring additional data.

Psychedelic therapy is NOT recreational use — it is a therapeutic process

The medical model is radically different from recreational use. Psychedelic therapy requires: preparation sessions (multiple sessions before the drug session, establishing therapeutic alliance, setting intentions, preparing for the experience); a guided dosing session (therapist present throughout 6-8 hours; monitored setting; safety protocol); integration therapy (multiple sessions after, processing and meaning-making). The drug creates a window of neuroplasticity; the therapy provides the context. This is not "take a pill and wait" — the therapeutic process is integral.

Mechanism — neuroplasticity and default mode network

Psilocybin activates 5-HT2A serotonin receptors → global increase in brain entropy; dramatic reduction in default mode network (DMN) activity (the self-referential, ruminative network overactive in depression); increased connectivity between previously disconnected brain regions; increased BDNF (neurotrophin promoting neuronal growth). The REBUS (Relaxed Beliefs Under Psychedelics) model (Friston and Carhart-Harris, 2019): psychedelics reduce the brain's rigid "top-down" predictive beliefs, creating a window for new psychological patterns. Ketamine: NMDA antagonism → glutamate surge → AMPA receptor activation → BDNF release → synaptogenesis — a different mechanism but related neuroplasticity outcome.

Contraindications and safety — serious adverse events are rare but real

Medical contraindications: personal or family history of psychosis or schizophrenia spectrum disorder (5-HT2A agonists can precipitate or worsen psychosis); bipolar I disorder; active suicidal ideation with plan; severe liver disease (psilocybin); cardiovascular risk (ketamine — blood pressure/heart rate increase). Drug interactions: psilocybin effect substantially reduced by SSRIs/SNRIs (chronic 5-HT receptor downregulation); serotonin syndrome risk (MDMA + SSRIs). HPPD (hallucinogen persisting perception disorder): rare but real — visual phenomena persisting after the psychedelic experience. Psychological adverse effects ("challenging experiences") are common (40-60% of subjects) but manageable with proper support.

Key statistics

FDA March 2019

esketamine (Spravato) approved for treatment-resistant depression

FDA 2019

29% remission

psilocybin 25mg vs 8% placebo at 3 weeks (COMPASS Phase 2b)

NEJM Evidence 2022

2 FDA BT

psilocybin received 2 FDA Breakthrough Therapy Designations (TRD 2018, MDD 2019)

FDA

Australia 2023

first country to approve psilocybin (TRD) and MDMA (PTSD) as medicines

TGA Australia 2023

2-4 hours

esketamine antidepressant onset (vs 4-6 weeks for SSRIs)

FDA/NEJM

1970

year psychedelic research was effectively halted by Schedule I classification

History

Psychedelic therapy — regulatory status and evidence by compound (2024-25)

Source: FDA/TGA/MAPS/COMPASS. Esketamine is the most regulated and established; psilocybin and MDMA are in Phase 3 review.

Glossary of key terms

Treatment-resistant depression (TRD)
WHO/PsychiatryDepression that has not responded to at least two adequate trials of antidepressants (adequate dose for adequate duration — typically 6-8 weeks at therapeutic dose) from at least two different pharmacological classes. Affects approximately 30% of people with major depressive disorder. TRD is associated with high disability, suicidality and healthcare costs. It is the target condition for esketamine (FDA-approved) and psilocybin (Breakthrough Therapy designation). TRD represents the unmet need that is driving psychiatric interest in psychedelic therapies.

5-HT2A receptor agonism — the psychedelic mechanism
NeuropharmacologyPsilocybin (prodrug converted to psilocin), LSD, mescaline and DMT are classical or "serotonergic" psychedelics — all activating the 5-HT2A receptor (a serotonin receptor subtype) in the prefrontal cortex, thalamus and other regions. This produces global changes in brain connectivity and information processing — measured as increased brain entropy on fMRI. Crucially different from MDMA (which is an entactogen — mainly releasing serotonin, dopamine and noradrenaline) and ketamine (NMDA antagonist). The 5-HT2A mechanism explains why SSRIs (which chronically downregulate 5-HT2A receptors) reduce psilocybin's effects.

Default mode network (DMN) and ego dissolution
NeuroscienceThe default mode network — medial prefrontal cortex, posterior cingulate cortex, precuneus, angular gyrus — is associated with self-referential thinking, mind-wandering and ego identity. In depression, the DMN is overactive and over-connected (rigid, ruminative self-referential thinking). Psilocybin produces dramatic acute DMN suppression, correlating with "ego dissolution" (dissolution of the sense of a separate self) — one of the most reliably reported subjective experiences. Post-session: DMN activity and rigidity may be reset to a less depressive pattern. This neurobiological mechanism may explain psychedelic therapy's antidepressant effects.

MDMA-assisted therapy for PTSD
MAPS/FDAMAPS's MDMA-assisted therapy model: MDMA (3,4-methylenedioxymethamphetamine) — a serotonin-releasing agent with empathogenic and entactogenic properties — reduces fear response and increases trust, enabling trauma processing in therapy sessions that would normally be too distressing. Protocol: 2-3 MDMA-assisted sessions (8 hours each, with therapist dyad present throughout) sandwiched between multiple non-drug psychotherapy sessions. MAPS Phase 3: CAPS-5 score (PTSD severity) improvement of approximately 24 points with MDMA vs approximately 14 points placebo; 67% no longer met PTSD diagnostic criteria vs 32% placebo. Australia TGA approved July 2023.

The psychedelic research blackout (1970-2000)
HistoryBetween 1943 (Hofmann's LSD synthesis) and 1970 (Controlled Substances Act), psychedelics were actively researched for depression, addiction, anxiety and existential distress — with promising early results. Timothy Leary's promotion of recreational LSD use, the 1960s counterculture, and political backlash led to the 1970 Controlled Substances Act scheduling LSD, psilocybin and MDMA as Schedule I (no medical use). Research effectively halted for approximately 25 years. The renaissance: Johns Hopkins received approval for psilocybin research in 2000 (Griffiths et al.); NYU, Imperial College London, COMPASS Pathways followed. The 25-year research gap delayed what may be transformative treatments.

Set and setting — the therapeutic context
MAPS/Psychedelic therapyTimothy Leary's observation, validated by modern research: the subjective experience and therapeutic outcome of a psychedelic session are profoundly influenced by "set" (mindset — the person's expectations, intentions, psychological state) and "setting" (the physical and social environment). Medical psychedelic therapy standardises both: careful screening and preparation to optimise set; standardised comfortable therapeutic setting with music, two trained therapists, safety protocol. This is why recreational use context (unscreened individuals, uncontrolled setting, no therapeutic support) produces fundamentally different outcomes than clinical settings — and why self-directed psychedelic use is not equivalent to psychedelic therapy.